The anti-tumor activity of retinoids has been proposed to be partially due to stimulatory effects on the immune system. To better understand their potential role in the prevention and treatment of human cancer, we are proposing to analyze, in detail, the effects of retinoids on human immune functions. The first objective of this proposal is to investigate specific mechanism(s) of immunomodulation which have already been demonstrated in vitro with retinoic acid (RA), with special emphasis on testing the hypothesis that RA exerts its immune stimulating effects by promoting lymphoid differentiation. To test this hypothesis, we will identify the phenotype of cells responding to RA treatment on the basis of cell surface markers which have been correlated to maturational stages or functional subsets of T cells. We will also study regulatory mechanisms involving lymphocyte mitogenic factors by which RA can influence lymphocyte responses. Our second aim is to study, in vitro, the effects of various other retinoid compounds on human immune functions, with a priority on investigating those derivatives currently being tested in clinical trials, as well as others which have been found to be the more biologically active in animal and in vitro test systems. Our final objective will be to assess immunological changes in individuals being treated with 13-cis retinoic acid in ongoing clinical trials. This study will involve analyzing the effects of the retinoid therapy on a number of cellular immune functions which may be relevant in anti-tumor reactions. This project should provide valuable information concerning the basic nature of the immunomodulating properties of retinoids in a human system. Such information is crucial for the proper evaluation of these compounds as prophylactic or therapeutic agents against neoplasia.